How Fat Regulates Cholesterol Absorption

It has been known for more than 40 years that dietary fat promotes cholesterol uptake, but fundamental aspects of that process remain poorly understood.

“One reason these questions remain unknown is because of the difficulty of studying such a complex biological system as the intestine,” which in addition to multiple cell types also includes a diverse array of enzymes, mucus, and symbiotic bacteria, he said.

“Because the larval zebrafish are optically clear, we can visualise fat transport and processing by looking right through their body wall into the intestine where the action is,” Walters said.

He developed a way to feed zebrafish a diet high in lipids (e.g., fat and cholesterol) or high in protein and low in lipids. He accomplished this by turning to the chicken egg, whipping fish water with the yolk for a high-lipid diet and the egg white as a high-protein diet. Before feeding these diets, fluorescently tagged cholesterol or fatty acid was added, enabling the microscopic viewing of how lipids are absorbed and processed by the intestinal cells.

Walters found that cholesterol was only absorbed when the fish ate a high-fat diet, not a low-fat diet. The fats and cholesterol were packaged into separate and clearly visible compartments within the cells. “You can tell which larvae had eggs for breakfast,” he said.

The researchers also found that some long-chain fatty acids, particularly a common one called oleic acid, were especially effective for promoting cholesterol uptake. They provided evidence that oleic acid acts to drive a cholesterol transport protein from within the intestinal cell to the cell surface, where it can interact with cholesterol passing through the gut and pull it into the cell.

Their findings suggest a tightly regulated system in which cholesterol is only taken up by the intestine in the presence of fats. One reason such regulation is important, Walters said, is that unprocessed cholesterol can be toxic to cells and requires fatty acid-mediated modification to render it safe in a process called esterification.